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Ashish S. Shah
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J Thorac Cardiovasc Surg 2009;137:1249-1257
© 2009 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model

Eric S. Weiss, MDa, Hunter C. Champion, MD, PhDb, Jason A. Williams, MDa, William A. Baumgartner, MDa, Ashish S. Shah, MDa,*

a Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md
b Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md

Received for publication May 13, 2008; revisions received November 25, 2008; accepted for publication December 30, 2008.

* Address for reprints: Ashish S. Shah, MD, Assistant Professor of Surgery, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N. Wolfe St, Baltimore, MD 21287. (Email: ashah29{at}jhu.edu).

Objectives: Ischemia–reperfusion injury remains a devastating complication of lung transplantation. Phosphodiesterase inhibitors have been shown to precondition tissues against ischemia–reperfusion injury. Little is known, however, about the utility of phosphodiesterase inhibition in reperfusion injury after lung transplantation. We evaluated the long-acting phosphodiesterase-5 inhibitor, tadalafil, in an ex vivo lung transplant model.

Methods: New Zealand White rabbits (4 kg), were given oral tadalafil (n = 11) 24 hours before lung harvest and compared with rabbits given oral vehicle alone (n = 11). Lungs were recovered with Perfadex solution (Vitrolife, Kungsbacka, Sweden) and cold stored for 18 hours. After storage, lung blocks were reperfused with donor rabbit blood in an ex vivo apparatus. Pulmonary artery pressures were recorded with serial arterial and venous blood gas sampling and animals served as their own controls. Phosphodiesterase-5 and protein kinase G tissue activity assays confirmed drug effects. Luminol chemiluminescence assay was used to measure reactive oxygen species and levels of endothelial and inducible nitric oxide synthase were measured.

Results: Extended cold storage, followed by reperfusion produced a consistent reproducible decrease in oxygenation and increase in pulmonary pressure. Tadalafil-treated animals exhibited greater PaO 2 throughout the course of reperfusion (P = .001) Mean pulmonary artery pressure was lower in tadalafil-treated animals (22 vs 40 mm Hg; P = .04). Phosphodiesterase-5 activity was decreased (143 ± 8 vs 205 ± 32 mP; P < .001) with protein kinase G activity increased (25 ± 12 vs 12 ± 2.4 fU/µg; P = .01) in the experimental group confirming that oral pretreatment resulted in active phosphodiesterase inhibition in the lung tissue. Reactive oxygen species (as measured by luminol activity) were decreased in tadalafil-treated animals (7.8 ± 1.5 vs 10.2 ± 1.2 relative light units; P = .003).

Conclusions: Our experimental model demonstrates that oral donor pretreatment with a long-acting phosphodiesterase inhibitor is an effective strategy for improving pulmonary performance after reperfusion. Importantly, phosphodiesterase enzymes and their downstream effectors may play a critical role in reperfusion injury after lung transplantation.

Abbreviations and Acronyms eNOS = endothelial nitric oxide synthase; GEE = generalized estimating equation; GMP = guanosine monophosphate; iNOS = inducible nitric oxide synthase; IR = ischemia and reperfusion; NO = nitric oxide; NOS = nitric oxide synthase; PA = pulmonary artery; PAP = pulmonary artery pressure; PCO 2 = partial pressure of carbon dioxide; PDE = phosphodiesterase; PGD = primary graft dysfunction; PKG = protein kinase G; PO 2 = partial pressure of oxygen; RM-ANOVA = repeated-measures analysis of variance; ROS = reactive oxygen species






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